Multiparticulate l-carnitine compositions and related methods

ABSTRACT

Enteric coated multiparticulate compositions that use a L-carnitine compound an active ingredient are disclosed. The multiparticulates have spheroidal core comprising a L-carnitine, microcrystalline cellulose, and hydroxypropyl methylcellulose; a sub-coat comprising hydroxypropyl methyl cellulose on the spheroidal core; and an enteric coat on the sub-coated spheroidal core. The average diameter of the particulates is about 0.1-3 mm. Other aspects of the invention include methods of making and methods of using the multiparticulate compositions.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority to U.S. Provisional Patent ApplicationSer. No. 61/494,053 filed on Jun. 7, 2011 titled “MultiparticulateFormulations Comprising L-Carnitine or a L-Carnitine Derivative andRelated Methods,” which is incorporated by reference herein in itsentirety.

FIELD OF THE INVENTION

The present invention relates to multiparticulate compositionscomprising the active ingredient L-carnitine or a derivative thereof,and more particularly, to controlled release multiparticulateformulations comprising L-carnitine or a derivative thereof and relatedmethods.

BACKGROUND

L-Carnitine is a naturally occurring compound that facilitates thetransport of fatty acids into the mitochondria for oxidation, andthereby energy production. It is a derivative of the amino acid lysine.Acetyl L-Carnitine (ALCAR) is an acetylated derivative of L-Carnitine.

Acetyl L-Carnitine

L-carnitine and its derivatives are used to treat carnitine deficiency,age related decline in mitochondrial function, cardiovascular disease(myocardial infarction, heart failure and angina pectoris), intermittentclaudication, end-stage renal failure, Alzheimer's disease, HIV/AIDS anddecreased sperm motility. In humans, the endogenous carnitine poolcomprises free L-carnitine and a range of short-, medium- and long-chainesterified carnitine derivatives, including acetyl-L-carnitine andpropionyl-Lcarnitine, for example. As a supplement taken orally, ALCARhas better bioavailability, than L-carnitine. Therefore, the esterifiedforms of L-carnitine may be considered as prodrugs of L-carnitine.

Unfortunately, some of the current techniques for administeringL-carnitine or its ester prodrugs to patients present several problems.Since L-carnitine and the derivatives ALCAR and propionyl-L-carnitinecan cause various side effects such as upset stomach, nausea andvomiting, it is desirable to administer L-carnitine, ALCAR, orpropionyl-L-carnitine in a manner that minimizes the manifestation ofthese side effects. Current administration techniques are hampered inthis regard because they present a small therapeutic window between whenthe benefits of L-carnitine, acetyl-L-carnitine, orpropionyl-L-carnitine take effect and when the side effects aremanifested.

SUMMARY OF THE INVENTION

In view of the foregoing, it is an object of the invention to provide acontrolled-release L-carnitine based composition that is adapted tominimize the side effects caused by carnitine, and provides for lessfrequent, more predictable, and reliable dosing by allowing carnitine topass through the stomach more quickly and to be dispersed throughout theintestinal tract.

In a composition aspect of the invention, a carnitine compositioncomprises a plurality of independently dispersible particulates, eachindependently dispersible particulate comprising: a spheroidal corecomprising about 30%-90% w/w of a carnitine, about 15%-70% w/wmicrocrystalline cellulose, and about 0.5%-1.5% w/w hydroxypropylmethylcellulose; a sub-coat on the spheroidal core, the subcoatcomprising hydroxypropyl methyl cellulose present in an amount of about2%-4% w/w of the independently dispersible particulates; and an entericcoat on the sub-coated spheroidal core, the enteric coat being about5%-15% w/w of the independently dispersible particulates; wherein theaverage diameter of the independently dispersible particulates is about0.1-3 mm.

The enteric coat may be selected from methacrylic acid co-polymer,cellulose acetate phthalate, polyvinyl acetate phthalate, or acombination thereof. Alternatively, the enteric coat may comprise apolymeric material that forms a film around the core and a pore formermaterial that generates pores in the film under intestinal pHconditions. In a particular embodiment, the polymeric material is ethylcellulose and the pore former material is sodium alginate.

In some embodiments, the composition further comprises a carnitinepermeation enhancer adapted to assist the carnitine to permeatebiological tissue. In a particular embodiment, the carnitine permeationenhancer is a p-glycoprotein efflux pump inhibitor such as, for example,polysorbate 80.

In some embodiments, the core further comprises a pellet, wherein thecarnitine is located on an outer surface of the pellet. The pellet maybe a non-pareil pellet or microcrystalline cellulose pellet, forexample.

The composition is preferably present in a pharmaceutically acceptabledosage form for being administered to a patient.

In a method of use aspect of the invention, a method of treating aphysiological condition in a patient comprises administering thecomposition of the invention to the patient. In a preferred embodiment,the physiological condition is selected from carnitine deficiency, agerelated decline in mitochondrial function, cardiovascular disease,myocardial infarction, heart failure, angina pectoris, intermittentclaudication, end-stage renal failure, Alzheimer's disease, HIV/AIDS,decreased sperm motility, or a combination thereof. Administering thecomposition to the patient may comprise administering a capsule havingthe independently dispersible particulates therein, combining thecomposition with an acidic food vehicle, or providing a blend of thecomposition and an acidic food vehicle to the patient through a feedingtube.

In a method of making aspect of the invention, a method of making acontrolled-release multiparticulate composition of L-carnitinecomprises: producing a spheroidal core comprising about 30%-90% w/w of acarnitine, about 15%-70% w/w microcrystalline cellulose, and about0.5%-1.5% w/w hydroxypropyl methylcellulose; coating the spheroidal corewith a sub-coat comprising hydroxypropropyl methylcellulose, thesub-coat being about 2%-4% w/w of the particulates in themultiparticulate composition; applying an enteric coat to the sub-coatedspheroidal core, the enteric coat being about 5%-15% w/w of theparticulates in the multiparticulate composition; and wherein theaverage diameter of particulates in the multiparticulate composition isabout 0.1-3 mm.

In some embodiments, the spheroidal core is produced by extrusion andspheronization. In a particular example, the spheroidal core is producedby blending the carnitine, microcrystalline cellulose, and hydroxypropylmethylcellulose with water to form a met mass and extruding the wetmass, cutting the extruded wet mass into pieces, spheronizing thepieces, and drying the spheronized pieces. The spheronized pieces arepreferably dried at a temperature of about 50° C.-60° C.

In some embodiments, the spheroidal core is produced by coating anon-pareil or microcrystalline cellulose pellet with the carnitine,microcrystalline cellulose, and hydroxypropyl methylcellulose.

These and other objects, aspects, and advantages of the presentinvention will be better appreciated in view of the following detaileddescription of the invention.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

In the Summary above and in the Detailed Description, reference is madeto particular features (including method steps) of the invention. It isto be understood that the disclosure of the invention in thisspecification includes all possible combinations of such particularfeatures. For example, where a particular feature is disclosed in thecontext of a particular aspect or embodiment of the invention, thatfeature can also be used, to the extent possible, in combination withand/or in the context of other particular aspects and embodiments of theinvention, and in the invention generally.

The term “comprises” is used herein to mean that other ingredients,steps, etc. are optionally present. When reference is made herein to amethod comprising two or more defined steps, the steps can be carried inany order or simultaneously (except where the context excludes thatpossibility), and the method can include one or more steps which arecarried out before any of the defined steps, between two of the definedsteps, or after all of the defined steps (except where the contextexcludes that possibility).

In this section, the present invention will be described more fully, inwhich preferred embodiments of the invention are detailed. Thisinvention may, however, be embodied in many different forms and shouldnot be construed as limited to the embodiments set forth herein. Rather,these embodiments are provided so that this disclosure will be thoroughand complete, and will convey the scope of the invention to thoseskilled in the art.

One aspect of the invention is to provide multiparticulate compositionscomprising L-carnitine or an L-carnitine derivative for treatingphysiological disorders related to a reduction of L-carnitine in thebody of a patient. As used herein, the term “L-carnitine” refers toL-carnitine and its esterified derivatives including acetyl-L-carnitineand propionyl-L-carnitine unless the context suggests otherwise.Examples of physiological disorders that may be treated with such amultiparticulate composition include L-carnitine deficiency, age relateddecline in mitochondrial function, cardiovascular disease (myocardialinfarction, heart failure and angina pectoris), intermittentclaudication, end-stage renal failure, Alzheimer's disease, Parkinson'sdisease, Peyronie's disease, insulin response deficiencies, HIV/AIDS,peripheral nerve injury, spinal cord injury, and decreased spermmotility.

Multiparticulate compositions of the invention advantageously permit theparticulates in the composition to pass to the intestines withoutsubstantially releasing L-carnitine in the stomach, thus preventing theundesirable side effects or reduced efficacy of L-carnitine that mayresult otherwise.

Further, because it is desirable for L-carnitine to be released into theintestines as opposed to the stomach, the composition provides reducedrelease in the stomach and an elevated release at a substantiallyneutral pH, such as the pH found in the intestines. As used herein, asubstantially neutral pH environment means an environment having a pH ofabout 7, including, but not limited to a pH of between about 6.5 toabout 7.5, also including the pH environment of the intestines.

The L-carnitine multiparticulate compositions of the invention providean advantageous L-carnitine non-parenteral delivery vehicle that can beadministered to a patient. A multiparticulate composition of theinvention comprises a plurality of individual particulates that arepreferably spheroidal in shape and are preferably configured forincorporation into a capsule or packet-type oral delivery dosage form.

The multiparticulates of the invention comprise a plurality ofparticulates which are preferably spheroidal in shape. Each particulateis sized to fit through the pyloric sphincter in a relaxed state. Thediameter of the particulates is preferably in the range of about 0.1-3mm, more preferably about 1-2.5 mm.

In certain embodiments, the particulates comprise a preferablyspheroidal core with an enteric coating over the core. The particulatesmay also have an optional sub-coating between the core and entericcoating. In a preferred embodiment, the sub-coating compriseshydroxypropyl methyl cellulose, also known as “HPMC” or “hypromellose.”The particulates may also include one or more additional coatings suchas a sealant coating or a color coating over the enteric coating.

The core comprises the primary active ingredient, an L-carnitine. Inpreferred embodiments, the L-carnitine is L-carnitine itself,acetyl-L-carnitine, and/or propionyl-L-carnitine. The core may alsocomprise one or more inactive ingredients.

The core may also include one or more of filler, stabilizer, binder,surfactant, processing aid, or disintegrant. By way of example only,suitable materials for performing these functions are provided. Asuitable filler includes a pharmaceutically suitable filler. In oneembodiment, the filler is microcrystalline cellulose. A suitable binderincludes a pharmaceutically suitable binder. In a preferred embodiment,the binder is a cellulosic water soluble polymer such as celluloseether. In one embodiment, a surfactant is added as a solubilizing agent,such as polysorbate 80. A suitable processing aid includes apharmaceutically suitable processing aid such as for improving theflowability of the core materials during processing. In a preferredembodiment, the processing aid is colloidal silicon dioxide. A suitabledisintegrant includes a pharmaceutically suitable disintegrant. In oneembodiment, the disintegrant is croscarmellose sodium.

A preferred composition for the core comprises about: 30-90% w/w of aL-carnitine; about 1% to 15% w/w processing aid; about 15 to 60% w/wfiller; about 4% to 6% w/w disintegrant; about 0.5% to 15% w/w binder;about 1% to 3% w/w solubilizing agent; and about 0.5% to 4% w/wantioxidant. Here the % w/w is relative to the total weight of theparticulate core.

A listing of ingredients for an exemplary embodiment of the core isshown in Table 1. In Table 1, the % w/w is based on the uncoated core.For the core, L-carnitine was supplied as 98% w/w L-carnitine/2% w/wCab-O-Sil M5P (Silicon Dioxide) and was milled using a granulationmixer. The % represents the theoretical quantity of L-carnitine in theblend. The core utilizes Avicel Ph102 as the filler.

The sub coating is a solution applied over the core. The sub coating ispreferably an additional layer of binder, such as from an about 10%Hypromellose solution.

The enteric coating is applied over the uncoated core or, if thesub-coating is present, over the sub-coating. The enteric coating ispreferably applied so that it comprises about 5-35% w/w of the entericcoated particulate. A preferred enteric coating material is amethacrylic acid based material such as a methacrylic acid-basedco-polymer. Examples of suitable methacrylic acid based copolymersinclude Eudragit L30D-55 or Kollicoat MAE 30 DP. These materials may becombined with other materials such as plasticizers for forming anenteric coating solution. In a typical embodiment, an enteric coatingsolution comprises about 20-70% w/w water, about 0.5-1.5% w/wplasticizer, about 3-15% anti-adherent, and about 25-70% copolymer. Byway of example only, a suitable plasticizer is triethyl citrate and asuitable anti-adherent is PlasACRYL T20.

A listing of the ingredients in an exemplary embodiment of entericcoated particulates is provided in Table 2. The % w/w is based on theweight of solution applied to the particulate.

Methods of making the multiparticulate compositions in accordance withanother aspect of the invention will now be described. The core istypically prepared by wet granulating the core materials into a wetmass, extruding the wet mass to form an extrudate, cutting the extrudateinto a plurality of core pieces, and spheronizing the core pieces. Thespheronized core pieces are preferably dried to <3% based on the KarlFischer method. The spheronized core pieces are then coated with theenteric coating material, which is typically applied in a fluidized bedcoater. The enteric coated particulates are subsequently dried, to <3%(Karl Fischer). The dried enteric coated multiparticulates may then beprepared into a suitable pharmaceutical dosage form such as a capsule ortablet, for example. A typical preferred capsule contains about 1000 mgof the particulates. Depending on the desired dosage, however, this maybe adjusted.

The multiparticulate compositions of the invention are preferablyformulated to be taken orally by a human or animal patient and to ensurethat the patient receives an effective amount of L-carnitine over thecourse of several hours after ingestion. An effective amount is anamount that is sufficient to affect a disease or process in the body. Ina preferred embodiment a dose of a multiparticulate composition providesabout 1000 mg to 3000 mg or, more preferably, about 2000 mg ofL-carnitine. Doses of the multiparticulate composition may beadministered sporadically. A patient may be a human or animal patient.

Accordingly, another aspect of the invention is to provide a method oftreating at least one of carnitine deficiency, age related decline inmitochondrial function, cardiovascular disease (myocardial infarction,heart failure and angina pectoris), intermittent claudication, end-stagerenal failure, Alzheimer's disease, HIV/AIDS and decreased spermmotility, the method comprising administering a multiparticulatecomposition of the invention to the patient (human or animal).

The multiparticulate compositions of the invention are preferablyformulated to be taken non-parenterally by a patient for treating one ormore physiological conditions that can be remediated by L-carnitine andderivatives thereof. In a method of use aspect of the invention, amethod of treating a physiological condition in a patient comprisesadministering a composition of the invention to the patient. The term“patient” refers to humans or other animals considered as having one ormore physiological conditions that can be remediated with L-carnitineand derivatives thereof. Examples of such physiological conditionsinclude serotonin deficiency, depression, weight loss, headaches,fibromyalgia, cerebellar ataxia, and insomnia. The term “administering”refers to the giving or applying of a substance. In a preferredembodiment, administering the composition to the patient includesadministering a capsule having the independently dispersibleparticulates therein.

In another preferred embodiment, administering the composition to thepatient includes combining the independently dispersible particulateswith an acidic food vehicle, such as an acidic, semi-solid food ordrink. This administration technique may be particularly useful withpatients who have difficulty swallowing. In such embodiments, theparticulates are preferably loaded into a sachet that the patient or acaregiver can easily open for sprinkling the particulates onto theacidic food vehicle. When the patient ingests the acidic food vehicle,the patient also ingests the particulates. Preferred acidic foodvehicles include food products like applesauce, fruit slurries, fruitjuices, or the like. In one embodiment of the invention, theindependently dispersible particulates are administered to a patientusing a feeding tube such as a gastric feeding tube, nasogastric feedingtube, or jejunostomy feeding tube.

Doses of the multiparticulate composition may be administeredsporadically when needed or may be administered as part of a long termtreatment.

These embodiments of the invention have many advantages. Some but notall of those advantages are listed here. Not all of the advantages arerequired by all embodiments of the invention.

One advantage of the multiparticulate compositions of the invention isthat they will provide a more reliable release of L-carnitine andderivatives thereof when compared to single-unit sustained releaseformulations that are presently available, without concern for dosing ofthe patient under the fed or fasted state. They will further provide aprolonged exposure to the L-carnitine and derivatives thereof bothlocally and systemically as compared to the single-unit sustainedrelease formulations. The use of multiparticulate formulations of thepresent invention comprising L-carnitine and derivatives thereof mayallow for less frequent dosing and may also allow for dosing with alower total amount of L-carnitine and derivatives thereof. Dispersion ofthe particulates in the lumen of the small bowel, prior to release ofthe L-carnitine, may reduce the incidence of side effects seen with theother carnitine formulations. Further, single unit sustained releaseformulations tend to release the L-carnitine and derivatives thereofonly in the local vicinity of the dosage form. The multiparticulatecompositions of the present invention can avoid this problem because theparticulates will disperse in the intestinal tract to provide adelocalized dose of L-carnitine and derivatives thereof therein.

EXAMPLE

This section describes an example of a preferred embodiment of theinvention. The example are not intended to limit the scope of theinvention in any way.

TABLE 1 Ingredients of an exemplary embodiment of the core. (grams/Ingredient % w/w) Ingredient Function L-Carnitine 935.9/78.4 Activeingredient Cab-O-Sil M5P 19.1/1.6 Processing Aid (Colloidal SiliconDioxide) Avicel (Micro 227.0/19.0 Filler Crystalline cellulose)Hypromellose 11.9/1.0 Binder (Methocel A15 Premium) Water (% of dry(15.0%) mass)

TABLE 2 Ingredients of an exemplary embodiment of enteric- coatedparticulates. Ingredient Ingredient (grams/% w/w) Function Kollicoat MAE30 506.6/85.8  Source of DP Solids methacrylic copolymer TriethylCitrate 75.7/12.8 Plasticizer PlasACRYL T20 7.9/1.3 Anti- AdherentWater¹ ¹Evaporates

Example Preparation of Multiparticulate Compositions

Experimental Details.

The equipment utilized to create the compositions herein includes thefollowing: top loading balances, hand screens (12, 14, 16, 18, Pan, 70mesh), Rotap sieve shaker, IKA mixer, KitchenAid food processor(pre-milling), Hobart mixer, LCI Benchtop Granulator, Fitz mill equippedwith a 0.065″ screen, Jet Mill, Key International high sheer mixer,Glatt GPCC-3 fluid bed drier, Glatt GPCC-3 fluid bed dried with 7″Wurster, Karl Fischer moisture analyzer, and a spheronizer.

Acetyl L-Carnitine Pre-Conditioning.

The Acetyl-L-Carnitine raw material contained large clumps of finecrystals. Also, the material is hygroscopic. It is necessary to de-lumpthe raw material and reduce the hygroscopicity in order to process thematerial. 500 g Acetyl-L-Carnitine (Lonza ALC Carnipure) and 10.2 gramsCab-O-Sil M5P (Cabot Corporation) were blended for 1-5 minutes in aKitchenAid Food Processor equipped with blade or similar blender andequipped with intensifier bar or pin bar.

Preparation of Core.

The core was prepared utilizing the following steps and settings. 955grams ALCAR/SiO₂ (98/2% w/w), 227 grams Microcrystalline Cellulose(Avicel Ph 102; FMC Corporation), and 11.9 grams Methocel A15 LV (Dow)were low shear granulated in a 0.5 Gallon (2 Liter) Hobart or othergranulation mixer and mixed at low speed for about 5 minutes. About162-172 g USP water was sprayed into the mixer to achieve peakgranulation moisture of about 12% to about 12.6% w/w, and this wasblended for about an additional 10-30 minutes to form a wet mass.

The wet mass was extruded through a 1.0 mm-hole perforated metal screenusing a LCI Benchtop Granulator at speed setting 10.

The extrudate was spheronized in 25-30 grams sub lots using a CalevaModel 120 spheronizer equipped with a small pyramid plate at high speedfor 2-3 minutes.

The combined spheronization sub lots (−1373 grams) were dried in aGPCG-3 or similar fluid bed dryer for about 45 minutes with an inlettemperature set point of 50° C. and a process air flow of 60 cfm.

The finished dried ALCAR multiparticulates were collected between12-mesh and 18-mesh screens resulting in a loose Bulk Density of about0.68 g/cc. A Camsizer particle size distribution analysis was performedfinding a size distribution of: DV₁₀ 1.002 mm, DV₅₀ 1.177 mm, and DV₉₀1.405 mm; a specific surface area (Sv) of 5.132/mm; and a specificsurface area (Sm) of 75.923 cm²/g.

Application of Sub-Coating.

1000 grams of ALCAR particulates were separated based on their size. Thefraction that fell within the 14-18 mesh size were chosen forsub-coating. The cores were placed into a Glatt GPCC-3 fluid bed drierand the sub-coating was sprayed onto the cores in the form of a 10%hypromellose (hypromellose E5) aqueous solution that was at roomtemperature.

The sub-coating solution (306 g USP Water (T>55° C.) and 34 ghypromellose E5) was applied to the cores using the followingparameters: the inlet temperature was maintained at about 50° C.; theair flow was maintained at about 50 cfm; the spray rate was maintainedbetween 6.0 and 11.0 g/min; and the filter shake cycle was 45/3 seconds(Time Between Shaking/Shaking Time). The fluid bed drier was setup witha 1.0 mm Schlick 970 nozzle port, and 2×360 air cap setting, a 1.5 cmpartition setting, and a multiparticulate bottom plate or equivalent.

Preparation of Enteric Coating Solutions.

The enteric coatings were applied to the cores in a fluidized bed coater(7″ wurster) as a liquid solution. The formula for the enteric coatingwas 1160 grams USP Water (RT), 506.6 grams BASF Kollicoat MAE 30 DP,75.7 grams PlasACRYL T20 (Colorcon), and 7.9 grams Triethyl Citrate USP,which was mixed a minimum of 20 minutes and screen through a 40-meshscreen prior to use.

The enteric coating solution was applied to 1000 grams of ALCARparticulate cores using the following parameters: the inlet temperaturewas maintained at about 50° C.; the air flow was maintained at about 50cfm; the spray rate was maintained between 6.0 and 11.0 g/min; theatomization air pressure was maintained at about 2.0 bar; and the filtershake cycle was 45/3 seconds (Time Between Shaking/Shaking Time). Thefluid bed drier was setup with a 1.0 mm Schlick 970 nozzle port, and2×360 air cap setting, a 1.5 cm partition setting, and amultiparticulate bottom plate or equivalent.

A finish coat may be applied over the enteric coating, and is applied ina same or similar manner as the enteric coating.

Unless otherwise defined, all technical and scientific terms used hereinare intended to have the same meaning as commonly understood in the artto which this invention pertains and at the time of its filing. Althoughvarious methods and materials similar or equivalent to those describedherein can be used in the practice or testing of the present invention,suitable methods and materials are described. The skilled shouldunderstand that the methods and materials used and described areexamples and may not be the only ones suitable for use in the invention.

Any publications, patent applications, patents, and other referencesmentioned herein are incorporated by reference in their entirety as ifthey were part of this specification. However, in case of conflict, thepresent specification, including any definitions, will control.

In the specification set forth above there have been disclosed typicalpreferred embodiments of the invention, and although specific terms areemployed, the terms are used in a descriptive sense only and not forpurposes of limitation. The invention has been described in some detail,but it will be apparent that various modifications and changes can bemade within the spirit and scope of the invention as described in theforegoing specification.

1. A composition comprising a plurality of independently dispersibleparticulates, each independently dispersible particulate comprising: aspheroidal core comprising about 30%-90% w/w of a L-carnitine, about15%-70% w/w microcrystalline cellulose, and about 0.5%-1.5% w/whydroxypropyl methylcellulose; a sub-coat on the spheroidal core, thesubcoat comprising hydroxypropyl methyl cellulose present in an amountof about 2%-4% w/w of the independently dispersible particulates; and anenteric coat on the sub-coated spheroidal core, the enteric coat beingabout 5%-15% w/w of the independently dispersible particulates; whereinthe average diameter of the independently dispersible particulates isabout 0.1-3 mm.
 2. The composition of claim 1, wherein the L-carnitineis at least one of L-carnitine, acetyl-L-carnitine,propionyl-L-carnitine, or a combination thereof.
 3. The composition ofclaim 1, wherein the enteric coat is selected from methacrylic acidco-polymer, cellulose acetate phthalate, polyvinyl acetate phthalate, ora combination thereof.
 4. The composition of claim 1, wherein theenteric coat comprises a polymeric material that forms a film around thecore and a pore former material that generates pores in the film underintestinal pH conditions.
 5. The composition of claim 4, wherein thepolymeric material is ethyl cellulose and the pore former material issodium alginate.
 6. The composition of claim 1, further comprising aL-carnitine permeation enhancer adapted to assist L-carnitine inpermeating biological tissue.
 7. The composition of claim 6, wherein thecarnitine permeation enhancer is a p-glycoprotein efflux pump inhibitor.8. The composition of claim 7, wherein the p-glycoprotein efflux pumpinhibitor is polysorbate
 80. 9. The composition of claim 1, wherein thecore further comprises a pellet and wherein the L-carnitine is locatedon an outer surface of the pellet.
 10. The composition of claim 9,wherein the pellet is a non-pareil or microcrystalline cellulose pellet.11. The composition of claim 1, wherein the multiparticulate compositionis present in a pharmaceutically acceptable dosage form.
 12. A method oftreating a physiological condition in a patient, the method comprisingadministering the composition of claim 1 to the patient.
 13. The methodof claim 12, wherein the physiological condition is selected fromcarnitine deficiency, age related decline in mitochondrial function,cardiovascular disease, myocardial infarction, heart failure, anginapectoris, intermittent claudication, end-stage renal failure,Alzheimer's disease, HIV/AIDS, decreased sperm motility or a combinationthereof.
 14. The method of claim 12, wherein administering thecomposition of claim 1 to the patient comprises administering a capsulehaving the independently dispersible particulates therein.
 15. Themethod of claim 12, wherein administering the composition of claim 1 tothe patient comprises combining the composition of claim 1 with anacidic food vehicle.
 16. The method of claim 12, wherein administeringthe composition of claim 1 to the patient comprises providing a blend ofthe composition and an acidic food vehicle to the patient through afeeding tube.
 17. A method of making a controlled-releasemultiparticulate composition of carnitine, the method comprising:producing a spheroidal core comprising about 30%-90% w/w of aL-carnitine, about 15%-70% w/w microcrystalline cellulose, and about0.5%-1.5% w/w hydroxypropyl methylcellulose; coating the spheroidal corewith a sub-coat comprising hydroxypropropyl methyl cellulose, thesub-coat being about 2%-4% w/w of the particulates in themultiparticulate composition; applying an enteric coat to the sub-coatedspheroidal core, the enteric coat being about 5%-15% w/w of theparticulates in the multiparticulate composition; and wherein theaverage diameter of particulates in the multiparticulate composition isabout 0.1-3 mm.
 18. The method of claim 17, wherein the spheroidal coreis produced by extrusion and spheronization.
 19. The method of claim 17,wherein the spheroidal core is produced by blending the carnitine,microcrystalline cellulose, and hydroxypropyl methylcellulose with waterto form a met mass, extruding the wet mass, cutting the extruded wetmass into pieces, spheronizing the pieces, and drying the spheronizedpieces.
 20. The method of claim 19, wherein the spheronized pieces aredried at a temperature of about 50° C.-60° C.
 21. The method of claim17, wherein the spheroidal core is produced by coating a non-pareil ormicrocrystalline cellulose pellet with the carnitine, microcrystallinecellulose, and hydroxypropyl methylcellulose.
 22. The method of claim17, wherein the L-carnitine is at least one of L-carnitine,acetyl-L-carnitine, propionyl-L-carnitine, or a combination thereof.